A predictive model to estimate fever after receipt of the second dose of Pfizer‐BioNTech coronavirus disease 2019 vaccine: An observational cohort study

Abstract Background and Aims Fever after coronavirus disease 2019 (COVID‐19) vaccination is generally a mild and benign event, but can cause excessive anxiety in younger adults. This study aimed to find key factors that include allergic diseases or physique that determine fever after vaccination. Methods We conducted an observational cohort study in our hospital to assess post‐COVID‐19 vaccination fever from April to June 2021. A total of 153 medical personnel aged 22–86 years of age were involved in the study to receive two doses, intramuscularly 21 days apart, of the Pfizer‐BioNTech COVID‐19 vaccine (30 μg per dose). Vaccination records were taken more than 72 h after vaccination. Clinical and laboratory variables (age, sex, allergy history, weight, height, serum hemoglobin concentration, and these derivatives) were examined by multivariable logistic regression analysis using the peak axillary temperature in the 4‐day period after the second vaccination as a dependent variable. Results No serious safety problems were detected. The incidence of a postsecond vaccination fever of 37.3°C or above was 29.4%. Logistic regression analysis found age, history of perennial allergic rhinitis, body surface area, body weight, percent overweight, and serum hemoglobin concentration as independent predictors of postvaccination fever. The characteristics of this individual were incorporated into the numerical model of human thermoregulation. The evaluation of this model had a sensitivity of 66.1% and a specificity of 90.7% in the detection of postvaccination fever. The multiple coefficient of determination (R 2) was 0.410. Conclusion The COVID‐19 vaccine induced higher rates of fever during the 4‐day period after the second vaccination. Younger age, part of the allergy history, small and light body, and concentrated blood were associated with postvaccination fever.


| INTRODUCTION
Coronavirus disease 2019 (COVID- 19) was declared a pandemic by the World Health Organization on March 11, 2020, 1 and the pandemic continues to worsen throughout the world. Elderly patients with underlying diseases and medical personnel are placed in a greater risk situation for COVID-19. 2 Although many drugs have been repurposed in the treatment of COVID-19, they remain supportive therapeutic options. [3][4][5] Safe and effective vaccines are urgently needed to control the COVID-19 pandemic. Two 30 μg doses of the Pfizer-BioNTech's mRNA COVID-19 vaccine (BNT162b2) were shown to improve an immune response with a high level of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) neutralizing antibodies and the reactogenicity profile of BNT162b2 showed transient local and systemic reactions. 6,7 Furthermore, achieving high vaccination coverage is critical to reduce COVID-19 associated mortality.
Fever can occur after every vaccination and has not been observed much in youth after COVID-19 vaccination. 7 Because vaccination-associated fever and anaphylaxis can cause young people to avoid COVID-19 vaccination, it is necessary to understand how individual factors impact fever. No study clearly showed that fever after COVID-19 vaccination is related to underlying allergic diseases and physique. In the present study, we used a multivariable statistical approach to identify an individualized model of human thermoregulation for stimulation of vaccination in adults. This study aimed to find key factors that include allergic diseases or physique that determine fever after vaccination.

| Study design and participants
A total of 163 medical personnel from our hospital were prospectively recruited in this observational cohort study from April 16 to June 23, 2021. One hundred and fifty-three eligible participants 22-86 years of age who were healthy or had stable chronic illnesses were assigned 30 μg of BNT162b2 (0.3 ml volume per dose), and given two doses, 21 days apart, injected into the deltoid muscle. The vaccination staff responsible for the safety evaluation observed people with a history of immediate allergic reactions to a vaccine or other drugs or any history of anaphylaxis for 30 min after vaccination.
All other participants were observed for 15 min after vaccination for any acute reactions. Body temperature was measured at the axilla using the conventional digital thermometer. Because postvaccination fever generally lasts about 48 h, 7 fever response was observed at least 72 h after vaccination. Each participant was instructed to record the temperature each day on a prospective diary card over 3 days after vaccination. Serious adverse events were recorded throughout the study period. Data on history and physical examination were compiled using a predesigned format. The percent overweight was determined using the following formula: ([actual body weight − standard weight]/Standard weight) × 100 (%). 8 Blood samples were taken from participants during their health check between June and September 2021. The clinical hematology laboratory performed a serum hemoglobin concentration assessment using the cyanmethemoglobin method (Bio Medical Laboratories). 9

| Definition of fever
The axillary temperature is used in routine clinical practice due to ease of use and safety, although the gold standard definition of a fever is a rectal temperature of 38°C or higher. 10 In this study, postvaccination fever was defined as an axillary temperature of 37.3°C or higher within the first 72 h of vaccination, because the mean difference in temperature (rectal minus axillary temperature) for the conventional digital thermometer was 0.85°C. 11 I advised the participants not to administer acetaminophen below their temperature of 37.3°C.

| Statistical analysis
The results were examined by univariable and multivariable analysis.
The variables entered into the multivariable logistic regression analysis were those with perceived clinical relevance, those identified by the univariable analysis in this study, or those reported as diagnostic value by other study. 12 Microsoft Excel.2010 was used for statistical calculations. Data are presented as mean (standard deviation) or percentages of participants. p < 0.05 was considered significant for all tests.
The effect size (Cohen's d) was calculated to quantify the size of differences between two groups, with values of 0.2-<0.5 considered as small, 0.5-< 0.8 as medium, and 0.8 or above as large. 13 3 | RESULTS

| Postvaccination fever
Fever after receiving the COVID-19 vaccine was reported more frequently by younger vaccine recipients (22-55 years old) than by older vaccine recipients (more than 55 years old) and more frequently after receiving the second dose than after the first dose. The frequency of fever (axillary temperature ≥37.3°C) after the first dose p < 0.01). Participants after the second vaccination represented significant differences in peak temperature with and without use of acetaminophen (37.3 [0.9]°C vs. 36.5 [0.6]°C; p < 0.01; Cohen's d = 1.08). Younger recipients were more likely to use acetaminophen for antipyretics or pain reliever (14% after first dose; 56% after second dose) than older recipients (9% after first dose; 28% after second dose).

| Adverse events
There were no serious events such as anaphylaxis or deaths related to vaccination. No adverse event causing withdrawal from the study was reported. But allergic reactions without anaphylaxis (n = 4), including persistent cough, rash, and swelling of the throat, occurred after receiving the first dose of the COVID-19 vaccine. All reported nonanaphylaxis allergic cases after receiving the vaccine occurred in women, not men. These cases underwent treatment with antihistamine (bilastine) in three (2%), corticosteroids (hydrocortisone sodium succinate) in one (0.7%) and fluticasone propionate/formoterol fumarate dehydrate in two (1%) ( Table 1).

| Analysis
Univariable regression analysis revealed that the peak axillary temperature after the second vaccination fever was negatively correlated with age, body weight, body surface area (BSA), percent overweight, or a history of lifestyle-related disease (hypertension or dyslipidemia) (Table 2). Similarly, the peak temperature was positively correlated with the BSA to body weight ratio, a history of perennial allergic rhinitis, or axillary temperature (15 min). The peak temperature did not correlate with sex or other allergies.
Each recipient is divided into a plurality of subgroups ( Figure 1). As expected, the peak axillary temperature after the second vaccination in younger vaccine recipients (<55 years old; n = 79) was greater than in older recipients (≥55 years old; n = 74), with a medium effect size (37.1   COVID-19 infection before vaccination was reported to be associated with a serious adverse effect of the COVID-19 vaccine in another study. 16 Fever may have a beneficial role in the prevention of infection. 24 The presence of postvaccination fever means that the immune system is building protection against invading pathogens, although high fevers can have detrimental effects on the host. 24 Acetaminophen was previously reported to have led to a reduction in fever rates after vaccination. 25 In the current study, prophylactic acetaminophen was not administered, but acetaminophen administered to participants for reasons other than fever (i.e., pain at the injection site) could possibly have masked some fever, making the observed fever rates less apparent. On the contrary, the peak temperature was actually higher in antipyretic vaccine recipients than those without antipyretics in another study, 26 which had the same result as this study. Therefore, we thought that the peak temperature was less affected by acetaminophen. On the other hand, antipyretics, including acetaminophen and corticosteroids, have been suggested to inhibit antibody production due to the anti-inflammatory effect, and antipyretic use is no longer recommended for vaccination-associated fever in Canada and New Zealand. 27 It is important to minimize the use of acetaminophen. Frequent intake of water and salt is recommended, although we should pay attention to the reduced cardiac and renal function of individuals with fever.
Regulation of body temperature is a fundamental homeostatic function in humans. This observational study highlights that younger age, part of the allergy history (perennial allergic rhinitis), morphological factors (small and light body), and a blood indicator of body water status (concentrated blood) are key regulators of a biological indicator of the inflammatory response to vaccination (high body temperature after vaccination). The peak temperature reported to us may be lower than the real temperature, as they do not want to go off work with suspected COVID-19. This may reduce sensitivity in this study. We evaluated postvaccination fever in our population.
However, this predictive model should be prospectively inspected in other population groups. Therefore, the purpose of the present study is not to continue its immediate use in practice, but to show a new tool for understanding vaccination-associated fever. Through more fine-tuning of the model that can predict vaccine-associated fever, this approach offers useful information to vaccine recipients, which is likely to ease fever phobia.

| Limitations of the study
Our single observational study has several limitations that should be considered when evaluating these results. First, the number of participants was relatively small for a definite conclusion to draw.
T A B L E 3 The independent predictors of postsecond vaccination fever selected in the logistic regression analysis

| CONCLUSIONS
This study demonstrated that younger age, a history of perennial allergic rhinitis, a small and light body, and a higher serum hemoglobin concentration are independent predictors of postsecond vaccination fever. Although the predictive model is not validated for direct clinical use, it illustrates the clinical potential of the technique used. If people are more aware of these factors of postvaccination fever and the elements of concern are removed, vaccination will go smoothly.
There is further discussion as to whether improving perennial allergic rhinitis and frequent intake of water and salt decrease the peak temperature after vaccination.

ACKNOWLEDGMENTS
The author thanks all the staff of the Medical Corporation Kenseikai who agreed to participate in this study, the chairman, the assistant directors, the other doctors, and all the nurses who cared for these participants, and all the technical and paramedical staff of the Sapporo Suzuki Hospital for their support in this difficult context.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

TRANSPARENCY STATEMENT
The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

ETHICS STATEMENT
This study was carried out according to the Declaration of Helsinki guidelines and was approved by the Ethics Committee of the Sapporo Suzuki Hospital (No. 2021-001, April 15, 2021) and the procedures were in accordance with institutional guidelines. Written informed consent was obtained from each study participant. We also obtained permission to publish our research results in writing. Before analyzing the data, all identifiable information was deleted and specific individuals cannot be identified by these data. Therefore, this was approved by the ethics committee.